Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1862, Issue 11, Pages 2098-2109Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2016.08.013
Keywords
Dihydrolipoamide dehydrogenase; Pathogenic mutation; E3 deficiency; Hydrogen/deuterium exchange; Mass spectrometry
Funding
- Hungarian Academy of Sciences (MTA grant) [02001]
- Hungarian Scientific Research Fund (OTKA) [112230]
- Hungarian Brain Research Program [KTIA_13_NAP-A-III/6]
- Bolyai Fellowship
- Fulbright Fellowship
- [NIH-R15GM116077]
- [NSF-CHE-1402675]
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Pathogenic amino acid substitutions of the common E3 component (hE3) of the human alpha-ketoglutarate dehydrogenase and the pyruvate dehydrogenase complexes lead to severe metabolic diseases (E3 deficiency), which usually manifest themselves in cardiological and/or neurological symptoms and often cause premature death. To date, 14 disease-causing amino acid substitutions of the hE3 component have been reported in the clinical literature. None of the pathogenic protein variants has lent itself to high-resolution structure elucidation by X-ray or NMR. Hence, the structural alterations of the hE3 protein caused by the disease-causing mutations and leading to dysfunction, including the enhanced generation of reactive oxygen species by selected disease-causing variants, could only be speculated. Here we report results of an examination of the effects on the protein structure of ten pathogenic mutations of hE3 using hydrogen/deuterium-exchange mass spectrometry (HDX-MS), a new and state-of-the-art approach of solution structure elucidation. On the basis of the results, putative structural and mechanistic conclusions were drawn regarding the molecular pathogenesis of each disease-causing hE3 mutation addressed in this study. (C) 2016 Elsevier B.V. All rights reserved.
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